Cawley Karen, Logue Susan E, Gorman Adrienne M, Zeng Qingping, Patterson John, Gupta Sanjeev, Samali Afshin
Apoptosis Research Centre, National University of Ireland, Galway, Ireland.
PLoS One. 2013 Aug 19;8(8):e73870. doi: 10.1371/journal.pone.0073870. eCollection 2013.
Global downregulation of microRNAs (miRNAs) is a common feature of human tumors and has been shown to enhance cancer progression. Several components of the miRNA biogenesis machinery (XPO5, DICER and TRBP) have been shown to act as haploinsufficient tumor suppressors. How the deregulation of miRNA biogenesis promotes tumor development is not clearly understood. Here we show that loss of miRNA biogenesis increased resistance to endoplasmic reticulum (ER) stress-induced cell death. We observed that HCT116 cells with a DICER hypomorphic mutation (Exn5/Exn5) or where DICER or DROSHA were knocked down were resistant to ER stress-induced cell death. Extensive analysis revealed little difference in the unfolded protein response (UPR) of WT compared to Exn5/Exn5 HCT116 cells upon ER stress treatment. However, analysis of the intrinsic apoptotic pathway showed that resistance occurred upstream of the mitochondria. In particular, BAX activation and dissipation of mitochondrial membrane potential was attenuated, and there was altered expression of BCL-2 family proteins. These observations demonstrate a key role for miRNAs as critical modulators of the ER stress response. In our model, downregulation of miRNA biogenesis delays ER stress-induced apoptosis. This suggests that disrupted miRNA biogenesis may contribute to cancer progression by inhibiting ER stress-induced cell death.
微小RNA（miRNA）的整体下调是人类肿瘤的一个常见特征，并且已被证明会促进癌症进展。miRNA生物合成机制的几个组成部分（XPO5、Dicer和TRBP）已被证明可作为单倍剂量不足的肿瘤抑制因子。miRNA生物合成失调如何促进肿瘤发展尚不清楚。在这里，我们表明miRNA生物合成的缺失增加了对内质网（ER）应激诱导的细胞死亡的抗性。我们观察到，具有Dicer低表达突变（Exn5/Exn5）或Dicer或Drosha被敲低的HCT116细胞对内质网应激诱导的细胞死亡具有抗性。广泛分析显示，内质网应激处理后，野生型与Exn5/Exn5 HCT116细胞的未折叠蛋白反应（UPR）几乎没有差异。然而，对内在凋亡途径的分析表明，抗性发生在线粒体上游。特别是，BAX激活和线粒体膜电位的消散减弱，并且BCL-2家族蛋白的表达发生改变。这些观察结果证明了miRNA作为内质网应激反应关键调节因子的关键作用。在我们的模型中，miRNA生物合成的下调延迟了内质网应激诱导的凋亡。这表明，破坏的miRNA生物合成可能通过抑制内质网应激诱导的细胞死亡而促进癌症进展。
